title: Induction of multipotential hematopoietic progenitors from human pluripotent stem cells via respecification of lineage-restricted precursors.
abstract: Human pluripotent stem cells (hPSCs) represent a promising source of patient-specific cells for disease modeling, drug screens, and cellular therapies. However, the inability to derive engraftable human hematopoietic stem and progenitor cells (HSPCs) has limited their characterization to in vitro assays. We report a strategy to respecify lineage-restricted CD34(+)CD45(+) myeloid precursors derived from hPSCs into multilineage progenitors that can be expanded in vitro and engrafted in vivo. HOXA9, ERG, and RORA conferred self-renewal and multilineage potential in vitro and maintained primitive CD34(+)CD38(-) cells. Screening cells via transplantation revealed that two additional factors, SOX4 and MYB, conferred engraftment. Progenitors specified with all five factors gave rise to reproducible short-term engraftment with myeloid and erythroid lineages. Erythroid precursors underwent hemoglobin switching in vivo, silencing embryonic and activating adult globin expression. Our combinatorial screening approach establishes a strategy for obtaining transcription-factor-mediated engraftment of blood progenitors from human pluripotent cells.
authors.affiliation: Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Manton Center for Orphan Disease Research, Howard Hughes Medical Institute, Children's Hospital Boston and Dana Farber Cancer Institute; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
authors.forename: Sergei
authors.initials: S
authors.lastname: Doulatov
authors.forename: Linda T
authors.initials: LT
authors.lastname: Vo
authors.forename: Stephanie S
authors.initials: SS
authors.lastname: Chou
authors.forename: Peter G
authors.initials: PG
authors.lastname: Kim
authors.forename: Natasha
authors.initials: N
authors.lastname: Arora
authors.forename: Hu
authors.initials: H
authors.lastname: Li
authors.forename: Brandon K
authors.initials: BK
authors.lastname: Hadland
authors.forename: Irwin D
authors.initials: ID
authors.lastname: Bernstein
authors.forename: James J
authors.initials: JJ
authors.lastname: Collins
authors.forename: Leonard I
authors.initials: LI
authors.lastname: Zon
authors.forename: George Q
authors.initials: GQ
authors.lastname: Daley
mesh_terms: D018952:Antigens, CD34 / Q000378:metabolism; D019070:Cell Lineage; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D006801:Humans; D017493:Leukocyte Common Antigens / Q000378:metabolism; D039902:Multipotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism
chemical_list: D018952:Antigens, CD34; D017493:Leukocyte Common Antigens